These studies are designed to broaden our knowledge of the physiology of gastric inhibitory polypeptide (GIP) and determine its possible contribution to the pathogenesis of diabetes mellitus. GIP is insulinotropic in normal subjects and glucagonotropic in diabetes. Its ability to stimulate insulin secretion appears to depend on the prevailing blood glucose level. To systematically examine the secretory response of GIP and its insulinotropic and glucagonotropic potential at various glucose levels a technique which clamps blood glucose will be used. GIP secretion has been found to be excessive in many but not all diabetics. We will determine the factors, i.e., insulin secretory reserve, obesity, duration of diabetes, presence of pancreatic glucagon, which are associated with the GIP excess of diabetes. To examine the putative role of insulin as an inhibitor of GIP secretion we will study the effect of GIP and glucagon of the physiologic replacement of insulin to diabetics using a technique designed by us. Furthermore, the effect of insulin on GIP will be studied in patients with insulinomas (model of endogenous hyperinsulinemia) by measuring GIP during fasting while the effect of hypoglycemia on GIP secretion is obviated by a glucose infusion. The autonomic nervous system may modulate GIP secretion and may mediate the serum GIP increase we have observed during insulin-induced hypoglycemia. We propose to study the effect of pharmacologic agonists and antagonists of various components of the autonomic nervous system on GIP secretion. Furthermore the effect of somatostatin on GIP secretion will be examined. Should either autonomic blockade and/or somatostatin impair GIP secretion studies using infusions of porcine GIP or glucagon will be carried out to determine the interactions between GIP and glucagon during hypoglycemia. Annually, 5000 diabetics and 10 patients with insulinomas are examined at the Mayo Clinic. There has been no difficulty in the past recruiting patients from these 2 groups for study. The proposed studies will be performed in the Clinical Study Unit of the Mayo Clinic. Hormonal radioimmunoassays will be performed in the Gastroenterology Research Unit and the Diabetes and Metabolism Research Laboratory.